Atherosclerosis is a chronic inflammatory cardiovascular disease (CVD) caused mainly due to dyslipidaemia, lipoprotein oxidation, disturbance of blood flow and endothelial dysfunction. Dyslipidemia is characterized by high levels of triglycerides, low levels of high density lipoproteins (HDL) and elevated levels of low-density lipoprotein cholesterol (LDL) concentrations in affected patients (Chapman M J, 2011). Atherosclerosis related CVD still remains the leading cause of worldwide morbidity and mortality. Clinical and epidemiological studies have demonstrated elevated level of LDL particles is an early event in initiation and progression of atherosclerosis. In addition, reduced HDL is known to be associated with increased risk of developing CVD. (Kishida K et al 2.012) The HDL particles are heterogeneous in shape, density, size, composition and they play a key role in athero-protective functions such as reverse cholesterol transport (RCT), anti-oxidant, anti-inflammatory, and antithrombosis (Kishida K et al 2013). The RCT mediated promotion of cholesterol efflux from foam cell macrophages of atherosclerotic lesions and its return to the liver for ultimate biliary excretions are important process by which HDL particles protect against atherosclerosis. It is scientifically well established that LDL and very low density lipoproteins (VLDL) promote atherosclerosis leading to the damage of blood vessels whereas HDL, act as an athero-protective system, to mitigate the damages on the blood vessel wall (McTaggart F, Jones P, 2008). Accordingly, reducing LDL particles and promoting HDL particles concentration by drugs is proven to reduce the risk of developing atherosclerosis related CVD.
Statin has become a leading cardiovascular medicine prescribed to treat patients for preventing both primary and secondary incidences of CVD (Davidson M H, 2005). Different types of statin drugs, brand names and their chemical structures are shown in the Table 1. Based on soluble property, statins are broadly divided into two categories such as hydrophilic and lipophilic. For example, statins such as pravastatin and rosuvastatin possess polar side groups bound to hydrophobic ring, rendering them hydrophilic, while pitavastatin, atorvastatin, lovastatin and simvastatin are classified as lipophilic. The difference in chemical structures of the statins plays a significant role in the metabolism of these drugs. For example, lovastatin and simvastatin, circulate in the blood as an inactive prodrug, whereas atorvastatin and rosuvastatin circulate as biologically active drugs. Active statins competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in the mevalonate pathway involved in cell mediated cholesterol synthesis (Endo A, 1992).
In addition, statins play important role in the clearance of circulating atherogenic LDL particles by up-regulating LDL receptors and thus contributing to about 24% reduction in CVD deaths as demonstrated in a number of clinical trials (Xanthopoulou I et al 2013). Although intensive use of statins leads to reduction in LDL levels the overall atherosclerosis related CVD mortality still remains high. It is being increasingly recognized that circulating levels of HDL are inversely correlated with CVD mortality suggesting HDL is an attractive target for statin and combination therapy to further reduce the residual risk from cardiovascular events (Chapman Mi et al, 2010).
Given the fact that statins are pleiotropic molecules and are being extensively used to treat CVD it is important to further understand their mechanism of action particularly related to lipid metabolism (Davignon J, 2012). Currently, there is no assay available to determine the effect of each statin on lipid particles formation in biological samples. Hence, there is a major need for the development of robust, reliable, and mechanism based assays.